Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in America, and, in 2011, 12.7 million US adults were estimated to have COPD. This disease is characterized by the progressive development of inflammation-induced airflow limitation, parenchymal destruction, and other systemic manifestations. Recognizing the limited advances in lung focused treatment options, it is of particular interest that skeletal muscle dysfunction is a frequent and clinically relevant systemic consequences of COPD that predicts morbidity and mortality, independently from the severity of lung function impairement. Several factors have been implicated in the development of muscle dysfunction with COPD, but oxidative stress has been suggested to play a major role. In other diseased states, also characterized by chronic oxidative stress (e.g. aging and cardiovascular disease), dysfunctional O2 transport and muscle metabolism in the periphery have been linked to both a lower nitric oxide (NO) bioavailability and nitric oxide synthase (NOS) uncoupling induced by a deficit in tetrahydrobiopterin (BH4). However, despite its potential as a novel target for therapeutic treatment, evidence of BH4 deficit-induced NOS uncoupling on the development of peripheral dysfunction with COPD is still lacking. Therefore, the goal of this project is to addres this gap in existing knowledge by elucidating the role of BH4 bioavailabiity and NOS coupling on peripheral O2 transport and muscle metabolism in patients suffering from COPD, with the prospective that BH4 supplemetation may be able to restore muscle function and improve the quality of life of these patients . Accordingly, during the K99 phase of this project, we will explre whether the severity of peripheral dysfunction assessed by several indices (perfusion/metabolism matching, limb blood flow, mitochondrial function in vivo and in permeabilized fibers, and contractile efficiency) during exercise in patients with COPD is related to the level of oxidative stress, as well as BH4 and NO bioavailability (Aim 1). We will then examine the effects of acute (Aim 2) and chronic (Aim 3) supplementations of BH4 on NOS coupling, the level of oxidative stress and NO bioavailability in the muscle and the vasculature, with the ultimate goal to restore skeletal muscle function and the functionnal capacity of these patients. To achieve these aims, we will use a comprehensive approach combining in vivo Near-Infrared Spectroscopy (NIRS), Doppler Ultrasound, Arterial Spin Labeling (ASL), and 31P-MRS measurements of O2 transport and muscle metabolism in exercising muscle, and in vitro methods utilizing molecular techniques to assess the level of oxidative stress, and permeabilized fibers to further interrogate mitochondrial respiration. At the conclusion of these studies, we will have expanded our knowledge of the mechanisms underlying muscle dysfunction in patients suffering from COPD, and, perhaps more important from a clinical perspective, provided insight into a potential novel therapeutic treatment for this disease.